This invention relates to galenic formulations which contain one or more members selected from the cyclosporin class.
Cyclosporins comprise a class of structurally distinct, cyclic, poly-N-methylated undecapeptides, generally possessing immunosuppressive, anti-inflammatory, anti-viral and/or anti-parasitic activity, each to a greater or lesser degree. The first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Ciclosporin, and its structure is given in The Merck Index, 11th Edition; Merck and Co., Inc.; Rahway, N.J., USA (1989) under listing 2759. Large numbers of other cyclosporins are also known and examples are disclosed in UK patent application No 2 222 770 A.
Cyclosporins are generally very insoluble in aqueous media. Consequently, severe difficulties have arisen in developing stable pharmaceutically acceptable formulations which allow delivery of the drug in sufficiently high concentrations to permit convenient use and which allow efficient and consistent absorption of the drug by the body. Problems also arise with regard to drug bioavailability and variability in patient dose response. Cyclosporins also have side effects at higher doses and therefore their concentration in the blood must be kept within certain therapeutic ranges. It is therefore desirable for the bioavailability of the cyclosporin drug to be as predictable and constant as possible.
In order to meet these and related difficulties, UK patent application 2 222 770 (the disclosure of which is incorporated by reference), discloses galenic formulations comprising a cyclosporin and which take the form of a microemulsion or microemulsion pre-concentrate. These formulations comprise a hydrophilic phase, a lipophilic phase and a surfactant. The following components for the hydrophilic phase are proposed: Transcutol, Glycofurol and 1,2-propylene glycol. Medium chain fatty acid triglycerides are disclosed as being suitable for the lipophilic phase. Reaction products of natural or hydrogenated vegetable oils and ethylene glycol are given as surfactants.
UK patent application 2 228 198 proposes an alternative means for meeting difficulties in relation to cyclosporin administration. Specifically it discloses oil based formulations in which the oily component comprises a combination of tri-glyceride and (i) glycerol partial esters or (ii) 1,2-propylene glycol complete or partial esters or (iii) sorbitol complete or partial esters. The products known and commercially available under the trade name MAISINE are proposed as suitable tri- and partial glyceride components. The disclosed compositions additionally comprise a surfactant component, for example Cremophor RH40. These may be preferably free of any hydrophilic components such as ethanol.
It has now surprisingly been found that simple, stable cyclosporin formulations that have improved bioavailability characteristics, reduced variability in inter- and intra-subject bioavailability parameters, are obtainable.
Accordingly this invention provides a pharmaceutical composition in the form of an emulsion preconcentrate and comprising a cyclosporin in a carrier medium, the carrier medium comprising: 1) a hydrophilic organic solvent, 2) (a) a mixed mono-, di-, and tri-glyceride or (b) a transesterified and polyethoxylated vegetable oil, and 3) a polyoxyethylene-sorbitan-fatty acid ester surfactant.
The pharmaceutical compositions are simple, stable, and provide surprisingly high bioavailabilities. For example, in clinical trials in which healthy volunteers each received three times 200 mg cyclosporin A in soft gelatin capsules under fasted and fed conditions, the pharmaceutical compositions resulted in at least a 150% increase in bioavailability as compared to the Cyclosporin market form which is disclosed in U.S. Pat. No. 4,388,307. Also, in the same trials, the relative bioavailability under fasted and fed conditions differed by less than 5%. This indicates very low inter-subject variability. Moreover intra-subject variability is reduced more than two fold. Hence the pharmaceutical compositions have very surprising properties which offer great advantages over the Cyclosporin market form.
The pharmaceutical composition is an emulsion preconcentrate; that is it has the characteristics of a stable emulsion preconcentrate system and spontaneously forms an emulsion in an aqueous medium, for example, in water or in the gastric juices after oral application. The emulsion formed is opaque, thermodynamically stable and contains dispersed droplets of a size greater than about 100 nm, more usually greater than about 200 nm. The pharmaceutical compositions are preferably emulsion preconcentrates of the type providing o/w (oil-in-water) emulsions.
The term xe2x80x9cpharmaceutical compositionxe2x80x9d as used in this specification means compositions of which the individual components or ingredients are themselves pharmaceutically acceptable. For example, where oral administration is foreseen, the components are suitable or acceptable for oral application.
The cyclosporin may be any cyclosporin having pharmaceutical utility as, for example, an immunosuppressive agent, an anti-parasitic agent or an agent for the reversal of multi-drug resistance. In particular the cyclosporin may be Cyclosporin A (also known as and referred to as Ciclosporin), and Cyclosporin G.
Suitably the pharmaceutical composition comprises from about 1 or 2 to 30%, preferably from 5 to 25% (more preferably from 7.5 to 15%, for example about 10%) by weight of cyclosporin based on the total weight of the pharmaceutical composition.
The hydrophilic organic solvent preferably comprises pharmaceutically acceptable, hydrophilic organic solvents which are suitable for oral administration. Examples are Transcutol, Glycofurol, ethyl acetate, propylene glycol and lower alkanols, or mixtures thereof. Preferred solvents are 1,2-propylene glycol and mixtures of 1,2-propylene glycol and ethanol. If the component (2) is a mixed mono-, di- and tri-glyceride, 1,2-propylene glycol and mixtures of 1,2-propylene glycol and ethanol are particularly preferred.
Suitably the hydrophilic organic solvent is present in an amount of from 1.0 to 50% (preferably from 5 to 40%, more preferably from 10 to 35%, and even more preferably from about 15 to about 30%) by weight based on the total weight of the carrier medium.
When the hydrophilic organic solvent comprises a mixture of 1,2-propylene glycol and ethanol, the co-component, that is the ethanol, is suitably present in an amount of up to about 20% (preferably up to about 15%, more preferably from about 5 to 15% and even more preferably 5 to 10%) by weight based in the total weight of the pharmaceutical composition. Thus the co-component is suitably present in an amount of from about 25 to 85% by weight based on the total weight of the organic solvent (for example 1,2-propylene glycol plus ethanol). More preferably the co-component is present in an amount of from 50% to 85%, for example from 70 to 80% based on the total weight of the hydrophilic organic solvent.
If component (2) comprises mixed mono-, di-, and tri-glycerides, the mixed mono-, di-, and tri-glycerides preferably comprise a mixture of C12-20 fatty acid mono-, di- and tri-glycerides. C16-18 fatty acid mono-, di- and triglycerides are especially preferred. The fatty acid component of the mixed mono-, di- and tri-glycerides may comprise both saturated and unsaturated fatty acid residues. Preferably however the mixed glycerides are predominantly comprised of unsaturated fatty acid residues, in particular C18 unsaturated fatty acid residues such as linolenic, linoleic and oleic acid residues. Suitably the mixed glycerides comprise at least 60%, preferably at least 75%, more preferably 85% or more by weight C18 unsaturated fatty acid mono-, di- and tri-glycerides. Suitably the mixed glycerides comprise less than 20%, for example about 15% or 10% by weight, saturated fatty acid mono-, di- and tri-glycerides (for example palmitic and stearic acid mono-, di- and tri-glycerides).
The mixed mono-, di-, and tri-glycerides are preferably predominantly comprised of mono- and di-glycerides. For example they comprise at least 50%, more preferably at least 70% (for example 75%, 80%, or 85% by weight) mono- and di-glycerides, based on the total weight of component (2)(a).
The mixed mono-, di-, and tri-glycerides suitably comprise from about 25 to about 50% (preferably from about 30 to about 40%, and more preferably about 35 to 40%) monoglycerides, based on the total weight of component (2)(a).
The mixed mono-, di-, and tri-glycerides suitably comprise from about 30 to about 60% (preferably from about 40 to about 55%, and more preferably about 45 to 50%) di-glycerides, based on the total weight of component (2)(a).
The mixed mono-, di-, and tri-glycerides suitably comprise at least 5% (preferably from about 7.5 to about 20%, and more preferably 9 to 15%) by weight of triglycerides, based on the total weight of component (2)(a).
The mixed mono-, di-, and tri-glycerides may be prepared by admixing individual mono-, di- or tri-glycerides in appropriate relative proportion. Conveniently however the mixed glycerides comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil, soybean oil, corn oil, sunflower oil or safflower oil, with glycerol. Preferably the vegetable oil is corn oil. Also mixtures of the oils may be transesterified with glycerol.
The transesterification products are generally obtained by heating the selected vegetable oil with glycerol to effect trans-esterification or glycerolysis. This may be carried out at high temperature in the presence of an appropriate catalyst, under an inert atmosphere and with continuous agitation. In addition to the mono-, di- and tri-glyceride components, the transesterification products also generally comprise minor amounts of free glycerol. However the amount of free glycerol in the mixed mono-, di-, and tri-glycerides is preferably less than 10%, more preferably less than 5%, most preferably about 1 to 2% by weight, based on the total weight of component (2)(a).
Preferably some of the glycerol is first removed (for example by distillation) to give a xe2x80x9csubstantially glycerol free batchxe2x80x9d, when soft gelatine capsules are to be made.
Trans-esterification products of corn oil and glycerol provide particularly suitable mixed mono-, di-, and tri-glycerides. An example of a suitable mixed glyceride product is the trans-esterification product commercially available under the trade name MAISINE. This product is comprised predominantly of linoleic and oleic acid mono-, di- and tri-glycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides (corn oil itself being comprised of about 56% by weight linoleic acid, 30% oleic acid, about 10% palmitic and about 3% stearic acid constituents). The physical characteristics of MAISINE [available from the company Etablissements Gattefossxc3xa9, of 36, Chemin de Genas, P.O. Box 603, 69804 Saint-Priest, Cedex (France)] are: up to 10% (typically 3.9 to 4.9% or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches, about 0.2%) free glycerol; about 35% (typically 30 to 40% or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches, about 32 to 36%, for example about 36%) mono-glycerides; about 50% (or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches about 46 to 48%) di-glycerides; about 10% (or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches, about 12 to 15%) tri-glycerides; and about 1% free oleic acid.
Further physical characteristics for MAISINE are: an acid value of maximum about 2, an iodine no. of about 85 to 105, a saponification no. of about 150 to 175 (Fiedler xe2x80x9cLexikon der Hilfsstoffexe2x80x9d, 3rd revised and expanded edition (1989) Vol. 2, p.768). The fatty acid content for MAISINE is typically: about 11% palmitic acid; about 2.5% stearic acid; about 29% oleic acid; about 56% linoleic acid; and 1.5% other acids.
It is especially preferred that the mixed mono-, di-, and tri-glycerides are clear and remain clear for more than 20 days upon storage at temperatures of 20xc2x0 C. to 25xc2x0 C. Also, a sample of the mixed mono-, di-, and tri-glycerides, which has been kept in a refrigerator at about between 2 and 8xc2x0 C. for 24 hours and then held at room temperature for 1 hour, should be clear.
Preferably the mono-, di-, tri-glycerides have a low saturated fatty acid content. Mixed mono-, di-, tri-glycerides meeting these requirements may be obtained from commercially available products by separation techniques as known in the art (for example freezing procedures coupled with separation techniques such as centrifugation) to remove the saturated fatty acid components and enhance the unsaturated fatty acid component content. Typically the total saturated fatty acid component content will be less than 15%, (for example  less than 10%, or  less than 5%) by weight based on the total weight of the component (2)(a).
A reduction of the content of saturated fatty acid component in the mono-glyceride fraction may be observed after being subjected to the separation technique. A suitable process is described in WO 93/09211.
Hence the mixed mono-, di-, tri-glycerides preferably contain lesser quantities of saturated fatty acids (e.g. palmitic and stearic acids) and relatively greater quantities of unsaturated fatty acids (e.g. oleic and linoleic acids) than the starting material.
A suitable example of a mixed mono-, di-, tri-glyceride product containing lesser quantities of saturated fatty acids contains: 32 to 36% mono-glycerides, 45 to 55% di-glycerides and 12 to 20% tri-glycerides, by weight based on the total weight of the lipophilic phase. Further characteristics include the following:
Mixed mono-, di-, tri-glycerides complying with these characteristics are referred to in this specification as xe2x80x9crefined glycerol-transesterified corn oilsxe2x80x9d. The xe2x80x9crefined glycerol-transesterified corn oilsxe2x80x9d have the advantage of remaining stable for a long time.
If components (2) comprises a transesterified and polyethoxylated vegetable oil, it preferably comprises transesterification products which are formed by transesterifying a vegetable oil triglyceride with a polyethylene glycol. Preferred transesterified and polyethoxylated vegetable oils are obtainable by transesterification of triglycerides from kernel oil, almond oil, ground nut oil, olive oil, soybean oil, maize oil, sunflower oil, safflower oil and/or palm oil, with one molar equivalent of a polyethylene glycol that has a molar weight between 200 and 800. These transesterified and polyethoxylated vegetable oils are available from GATTEFOSSÉ, Saint-Priest Cedex, France, under the trade name LABRAFIL (Fiedler loc cit, Vol. 2, page 707). A preferred transesterified and polyethoxylated vegetable oil is LABRAFIL 2125 CS (oleic acid linoleic acid glyceride from maize oil) having an acid number of 2, a saponification number of 155 to 175 and an iodine number of 90 to 110. Another example is LABRAFIL M 1944 CS (obtained from kernel oil and having an acid number of about 2, a saponification number of 145 to 175 and an iodine number of 60 to 90). LABRAFIL M 2130 CS (which is a transesterification product of a C12-18 glyceride and polyethylene glycol and which has a melting point of about 35 to 40xc2x0 C., an acid number of less than about 2, a saponification number of 185 to 200 and an iodine number of less than about 3) may also be used. The preferred transesterified ethoxylated vegetable oil is LABRAFIL M 2125 CS.
The transesterification products are generally obtained by heating the selected vegetable oil with polyethylene glycol to effect transesterification. This is done at high temperature in the presence of an appropriate catalyst under an inert atmosphere with continuous agitation. This process is described in U.S. Pat. No. 3,288,824.
The transesterified and polyethoxylated vegetable oil may also comprise esters of saturated or unsaturated C12-20 fatty acids with glycerol or propylene glycol, for example glycerol monooleate. Products of this type are known and commercially available.
Suitably component (2) is present in the pharmaceutical compositions in an amount of from 5 to 65%, preferably from 15 to 45%, more preferably from 20 to 40%, and even more preferably from about 25 to about 40%, based on the total weight of the carrier medium.
The polyoxyethylene-sorbitan-fatty acid ester surfactant preferably has an HLB of at least 10. Examples of suitable polyoxyethylene-sorbitan-fatty acid ester surfactants are mono- and tri-lauryl, palmityl, stearyl and oleyl esters such as those known and commercially available under the trade name TWEEN (Fiedler, loc.cit. p.1300-1304). Examples include the TWEEN
20 [polyoxyethylene(20)sorbitanmonolaurate],
21 [polyoxyethylene(4)sorbitanmonolaurate],
40 [polyoxyethylene(20)sorbitanmonopalmitate],
60 [polyoxyethylene(20)sorbitanmonostearate],
65 [polyoxyethylene(20)sorbitantristearate],
80 [polyoxyethylene(20)sorbitanmonooleate],
85 [polyoxyethylene(20)sorbitantrioleate].
Especially preferred TWEEN 20 and TWEEN 80.
Suitably the polyoxyethylene-sorbitan-fatty acid ester is present in the pharmaceutical compositions in an amount of from 25 to 75% (preferably from 30 to 60%, more preferably from about 30 or 40%) based on the total weight of the carrier medium.
The pharmaceutical composition may further include (4) water, in which case the pharmaceutical composition is in the form of a stable emulsion.
The pharmaceutical composition may also include further additives or ingredients, for example antioxidants (such as ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols) and/or preserving agents. These additives or ingredients may comprise about 0.05 to 1% by weight of the total weight of the pharmaceutical composition. The pharmaceutical composition may also include sweetening or flavoring agents in an amount of up to about 2.5 or 5% by weight based on the total weight of the pharmaceutical composition. Preferably the antioxidant is xcex1-tocopherol (vitamin E).
The pharmaceutical composition has been found to exhibit especially advantageous properties when administered orally in terms of both the consistency and high level of bioavailability achieved as indicated in standard bioavailability tests and clinical trials. Hence the pharmaceutical composition provides an improved oral administration form for cyclosporins (e.g. Ciclosporin) as it exhibits absence of significant food interaction, which has been observed with the commercially available oral form of Ciclosporin, especially with fat, rich food. Moreover, inter-subject and intra-subject variability of pharmacokinetic parameters are significantly lower than with the commercially available oral form of Ciclosporin. Thus the pharmacokinetic parameters (for example absorption and blood levels), become surprisingly more predictable and this reduces problems which have occurred previously with erratic absorption of Ciclosporin.
Additionally the pharmaceutical composition exhibits improved bioavailability in patients having malabsorption, for example liver transplantation patients or pediatric patients. Further the pharmaceutical composition is compatible with tenside materials, for example bile salts, present in the gastro-intestinal tract. That is, the pharmaceutical composition is fully dispersible in aqueous systems comprising such natural tensides and is thus capable of providing emulsion systems in situ which are stable and do not exhibit precipitation of the active ingredient or other disruption of fine particulate structure. The function of the pharmaceutical composition upon oral administration remains substantially independent of and/or unimpaired by the relative presence or absence of bile salts at any particular time or for any given individual.
The pharmaceutical composition is preferably compounded into unit dosage form, for example by filling it into orally administrable capsule shells (for example soft or hard gelatine capsule shells) but, if desired, may be in drink solution form. Where the pharmaceutical composition is in unit dosage form, each unit dosage suitably contains between 10 and 200 mg cyclosporin, more suitably between 10 and 150 mg, for example 15, 20, 25, 50 or 100 mg cyclosporin. Such unit dosage forms are suitable for administration 1xc3x97, 2xc3x97, 3xc3x97 and up to 5xc3x97 daily (for example, depending on the particular purpose of therapy, the phase of therapy, etc.).
The utility of the pharmaceutical composition can be observed in standard clinical tests in, for example, known indications of cyclosporins at dosages giving equivalent blood levels of cyclosporins; for example using dosages in the range of 25 mg to 1000 mg of cyclosporin per day for a 75 kilogram adult and in standard animal models. The increased bioavailability of the active ingredient provided by the compositions can be observed in standard animal tests and in clinical trials, for example as set out in Examples 4 and 5.
The optimal dosage of cyclosporin to be administered to a particular patient must be considered carefully by the treating physician as individual response to and metabolism of the cyclosporin may vary. It may be advisable to monitor the blood serum levels of the cyclosporin by radioimmunoassay, monoclonal antibody assay, or other appropriate conventional means. Dosages of the cyclosporin will generally range from 25 mg to 1000 mg per day for a 75 kilogram adult, preferably 50 mg to 500 mg. Satisfactory results are obtained by administering capsules containing 50 mg or 100 mg cyclosporin in amounts to make up a dose as needed.
In another aspect the invention also provides a process for the production of a pharmaceutical composition as defined above, which process comprises admixing a cyclosporin; an organic solvent; a mixed mono-, di-, and tri-glyceride or a transesterified and polyethoxylated vegetable oil; and a polyoxyethylene-sorbitan-fatty acid ester. If required, the obtained pharmaceutical composition may be compounded into unit dosage form.
In a more particular embodiment, the components are admixed such that an emulsion preconcentrate and, when required, combining the obtained pharmaceutical composition with sufficient water or sufficient of an aqueous solvent medium such that an emulsion is obtained.
The following examples are illustrative of the pharmaceutical composition, in unit dosage form, suitable for use, for example in the prevention of transplant rejection or for the treatment of autoimmune disease, on administration of from 1 to 5 unit dosages/day. The examples are described with particular reference to Ciclosporin and [0-(2-hydroxyethyl)-(D)-Ser]8-Ciclosporin (referred to as Compound Z in this specification). However equivalent pharmaceutical compositions may be obtained employing any other cyclosporin.